lecture 31: diseases and disorders 3: uterine

Question 1

What is gynaecology?

Answer 1

• gynaecology is a medical speciality focued on women’s health, in particular the genital tract in non-pregnant women (ovaries, uterus, vagina)
• a gynaecologist manages medical and surgical problems affecting women’s reproductive and urological systems
• problems with menstruation
• lower abdominal pain
• gynaecologic malignancies
• fertility problems
• sexual health
• sexually transmitted diseases
• urinary incontinence

Question 2

What is the human menstrual cycle?

Answer 2

Question 3

What are normal limits for menstrual bleeding?

Answer 3

• frequency of menses (days)
  
  • frequent: less than 24
  • normal: 24-38
  • infrequent: more than 38
• regularity of menses: cycle-to-cycle variation over 12 months, days
  
  • absent: no bleeding
  • regular: variation ± 2-20
  • irregular: variation more than 20
• duration of flow, days
  
  • prolonged: more than 8.0
  • normal: 4.5 - 8.0
  • shortened: less than 4.5
• volume of monthly blood loss, mL
  
  • heavy: more than 80
  • normal: 5 - 80
  • light: less than 5
• abnormal uterine bleeding (AUB) occurs when menstrual uterine bleeding falls outside normal parameters
• unscheduled bleeding between menstrual cycles is also categorised as abnormal

Question 4

What is PALM-COEIN?

Answer 4

• classification system for causes of abnormal uterine bleeding in the reproductive years
• women may fit into more than one category
• Polyps
• Adenomyosis
• Leiomyoma (uterine fibroids)
• Malignancy and hyperplasia
• Coagulopathy (clotting disorders e.g. von Willebrand disease)
• Ovulatory disorders
• Endometrium
• Iatrogenic (non-menstrual bleeding or spotting due to hormonal therapies)
• Not classified

Question 5

What is Heavy Menstrual Bleeding (HMB)?

Answer 5

• Menorrhagia definition: excessive menstrual blood loss which interferes with the woman’s physical, emotional, social and material quality of life
• normal average monthly menstrual blood loss (MBL) = 35 mL
  
  • HMB usually defined as MBL more than 80ml (=90th per centile)
  • HMB: increased incidence of iron deficiency and anaemia
• incidence:
  
  • affects 10-30% of menstruating women
  • increases up to 50% peri-menopause
• costs:
  
  • social, medical and public health issue
  • economic implications (e.g. treatment costs, lost work days)

Question 6

What are treatments for HMB?

Answer 6

• treatment depends on cause and life stage of the women
• medical:
  
  • hormonal:
    
    • combined oral contraceptive pill
    • progestogens e.g.: Mirena - intrauterine device that releases Levonorgestrol
  • prostaglandin synthetase inhibitors (e.g. megenamic acid)
    
    • block prostaglandin production (prostaglandins have roles in inflammation, vessel function, platelet aggregation etc)
  • anti-fibrinolytic agents (e.g. Tranexamic acid)
    
    • fribrinolysis: process that dissolves fibrin resulting in removal of small blood clots
• surgical:
  
  • endometrial ablation: removal of lining of uterus
  • hysterectomy: surgical removal of the uterus
• management of iron deficiency

Question 7

Why is HMB research difficult?

Answer 7

• limited research - no animal models
• observation studies using human tissue samples
• basic studies on mechanisms of mesntruation
• clinical trials comparing treatments
• NHMRC Funding Research Project: Mechansisms of Heavy Menstrual Bleeding (Hickey, Rogers and Girling)
  
  • Aim: understand the molecular mechanisms playing a role in HMB associated with common clinical presentations:
    
    • regular menstrual cycles with/without uterine fibroids
• investigate pathways already known to have a role in HMB
• identify novel pathways involved in HMB

Question 8

What are uterine fibroids?

Answer 8

• Leiomyoma: benign clonal tumours of the smooth muscle cells of the uterine muscle wall (myometrium)
• incidence:
  
  • most common benign tumour in fertile women
  • affect around one third of women aged 18-30 years and 50-80% of women by age 50
  • incidence and severity is higher in women of african descent
  • main indication for hysterectomy
• key symptoms
  
  • not all fibroids are symptomatic
  • heavy menstrual bleeding
  • pain symptoms
  • fertility and pregnancy problems
• costs
  
  • negative effects on quality of life
  • high personal and healthcare costs

Question 9

What are features of fibroids?

Answer 9

• fibroids are heterogeneous
• firm, round outline well demarcated from surrounding myometrium
• single or multiple
• vary in size
• variable in location:
  
  • submucosal
  • intramural
  • subserosal
  • pedunculated
• bundles of differentiated smooth muscle cells (SMC), fibrous tissue, sparse vasculature, few mitotic figures

Question 10

Images of fibroids

Answer 10

Question 11

What are symptoms of uterine fibroids?

Answer 11

• approximately 25% of women with fibroids have clinical symptoms
• incidence and severity of symptoms depends on size, number and location of fibroid
• distortion of uterine cavity or surface
• irregular or excessive/heavy menstrual bleeding (which may be associated with anaemia)
• pelvic pain or pressure
• bowel and bladder dysfunction
• fertility problems
• recurrent miscarriage

Question 12

What are non-surgical treatments of uterine fibroids?

Answer 12

• treatments tailored to individual patient based on severity of symptoms, and age and proximity to menopause
  
  • is fertility preservation required?
  • side effects
• medical treatments:
  
  • GnRH analogues: may be used to induce hypoestrogenic state to shrink tumours before surgery
    
    • short term use only
    • effects on fibroid growth temporary
    • side effects
  • progestins (e.g. mirena): to reduce HMB
  • hormone modulators e.g. SERM, SPRMS

Question 13

What are surgical interventions used to treat uterine fibroids?

Answer 13

• hysterectomy: removal of uterus
• myomectomy: removal of uterine fibroid
• uterine artery embolization: delivery of particulate material through the uterine arteries to block the blood supply to vessels of the uterine fibroid
• magnetic resonance-guidance focused-ultrasound (MRgFUS): application of high-intensity focused ultrasound energy to locally heat and destroy diseased or damaged tissue through ablation
  
  • leads to thermal destruction of fibroid
  • only suitable for certain types of fibroid

Question 14

What are fundamental factors involved in myometrial physiology and uterine leiomyoma formation and growth?

Answer 14

• genetic factors:
  
  • chromosomes 2, 3, 6, 7, 8, 10, 11, 12, 13, 14, 22
  • genes - MED12, HMGA2, HMGA1, FH, BHD, TSC2, PCOLCE, ORC5L and LHFPL3
• risk factors:
  
  • early menarche
  • age (late reproductive years)
  • heredity
  • nulliparity
  • obesity
  • PCOS
  • diabetes
  • hypertension
• cytokines
  
  • IL1, 6, 11, 13, 15
  • TNFalpha
  • GM-CSF
  • erythropoietin
• epigenetic factors:
  
  • DNA methylation, histone modifciation, miRNA (let7, miR-21, miR-93, miR-106b, and miR-200)
• ECM components:
  
  • collagen, fibronectin and proteoglycans
  • chemokines:
    
    • MIP1alpha, MIP-1beta
    • RANTES
    • eotaxin, eotaxin-2
    • IL-8
    • CCR1, CCR3, CCR5
    • CXCR1, CXCR2
    • MCP-1
• growth factors
  
  • EGF, HB-EGF, PDGF, IGF, TGF-alpha, TGF-beta, VEGF, aFGF, bFGF
  • activin and myostatin
• progesterone
• oestrogen

Question 15

What is research on uterine fibroids?

Answer 15

• despite scale of problem - limited research
• heterogeneity not necessarily recognised in study design
• lack of suitable animal models
• observational studies:
  
  • comparing fibroid and host myometrium, regressing and growing fibroids for expression of growth factors, receptors etc
• in vitro studies:
  
  • using cultured fibroid and host myometrial SMCs for examining interactions between ER, PR and growth factors etc
  • But! cultured cells may not be representative of what goes on in vivo
• examples of our research:
  
  • retinoid pathway: Zaitseva et al
  • differential gene and protein expression - contribution to mechanisms? Zaitseva et al
  • fibroid heterogeneity: zhao and rogers, tsiligiannis
  • using MRgFUS to investigate how symptomatic fibroids cause heavy menstrual bleeding

Question 16

What is endometriosis?

Answer 16

• presence of oestrogen-dependent endometrial lesions containing glands and stroma outside of the uterus
• incidence
  
  • 6-10% of reproductive-aged women
  • 50-60% of women with pelvic pain
  • 30-50% of women with infertility
• key symptoms
  
  • various pain symptoms
  • fertility problems
• costs
  
  • negative effects on quality of life: mental, social and physical wellbeing
  • high personal and healthcare costs

Question 17

What are common locations for endometriosis?

Answer 17

• endometrial implants/lesions
• endometrial nodules
• endometriomas
• umbilicus
• coecum
• peritoneum
• appendix
• bladder
• uterine serosa
• uterovesical fold
• rectovaginal septum and uterosaccral ligaments
• sigmoid colon
• ovary
• ureter
• fallopian tube
• small bowel

Question 18

What are the symptoms of endometriosis?

Answer 18

• complicated range of pain symptoms - symptoms can overlap with other disorders
• women may be asymptomatic or symptomatic
• key symptoms: pain, infertility and/or HMB
• pain symptoms include (but not limited to):
  
  • dysmenorrhea (menstrual period pain)
  • pyspareunia (pain during sexual intercourse)
  • non-menstrual pelvic pain
  • lower back pain
  • ovulation pain
• bowel and bladder symptoms
• fatigue
• fertility problems
• women with endometriosis are at increased risk of autoimmune disease, ovarian cancer (endometriod and clear-cell), and other cancers (e.g. non-Hodgkin’s lymphoma, melanoma)

Question 19

How is endometriosis diagnosed?

Answer 19

• often a delay from onset of symptoms until diagnosis of endometriosis. Research suggests a mean delay of 6.7 years
• definitive diagnosis requires surgery (laparoscopy) to visualise the lesions

Question 20

How can endometriosis be treated?

Answer 20

• multi-disciplinary: surgical, medical, and management approaches (e.g. psychology, physiotherapy)
• surgery:
  
  • removal of lesions and adhesions - often by laparoscopy
  • sometimes hysterectomy
• medical:
  
  • manipulation of hormones to produce a pseudo-pregnant or pseudo-menopausal state (amenorrhea)
    
    • androgens e.g. danazol
    • GnRH antagonists e.g. zoladex
    • progestogens e.g. Mirena
    • combined oral contraceptives
• pain relief: analgesics, NSAIDs
• side effects have to be considered
• symptoms often recur after treatment

Question 21

What are theories about the aetiology of endometriosis?

Answer 21

• no one theory can explain all aspects of the pathology
• mesothelium, other cell types → metaplasia
• mullerian rests → induction
• E2
  
  • environment
  • inflammation
  • genetics
• lymphatic spread, haematogenous spread
• bone marrow
  
  • mesenchymal
  • haematopoietic stem cells
  • endothelial precursors
  • endometrial tissue and cell reflux

Question 22

Do implants arise from uterine endometrium?

Answer 22

• retrograde menstruation theory: explains physical displacement of endometrial fragments into the peritoneal cavity, but not the development of lesions
• retrograde menstruation occurs in 90% of women, but endometriosis only develops in 10%
• also need:
  
  • escape from immune clearance
  • attachment to peritoneal epithelium
  • invasion of the epithelium
  • establishment of blood vessels and innervation
  • continued growth and survival

Question 23

Do implants arise from tissues other than uterus?

Answer 23

• coelomic metaplasia: transformation of normal peritoneal tissue to endometrial tissue
• induction theory: an endogenous stimulus, such as hormone, promotes differentiation of cells in the peritoneal lining to endometrial cells
• embryonic mullerian rests: cells residual from embryologic mullerian duct migration maintain the capacity to develop into endometriotic lesions under the influence of oestrogen
• extrauterine stem or progenitor cells from bone marrow may differentiate into endometriotic tissue
• benign metastasis: lesions result from lymphatic or haematogenous (via blood) transport of endometrial cells

Question 24

What are features of the pathophysiology of endometriosis?

Answer 24

• genetics vs environment
  
  • hereditable component to endometriosis
  • risk for first-degree relatives of women with severe endometriosis is 6 times higher than relatives of unaffected women
• increased endometrial cell survival
  
  • acquired genetic alterations – endometrial cells have high turnover and are therefore vulnerable to genetic recombination errors
• altered hormonal activity
  
  • oestrogen (E) dependence
  • localised E production by lesions
  • progesterone (P) resistance - deregulated activity of P in lesions and uterus
• dysregulation of immune clearance and refluxed endometrial cells
• endometrial cell invasion and attachment
  
  • shares features with malignancy
  • matrix metalloproteinase activity
• angiogenesis and neuroangiogenesis
  
  • growth of blood vessels into lesions
  • growth of nerve fibres/axons into lesions
• inflammation
  
  • increased number of activated macrophages in women with endometriosis
  • altered cytokine/chemokine profile
  • increased prostaglandins in peritoneum

Question 25

What are endometriosis research directions?

Answer 25

• epidemiology
  
  • environment
  • BMI
  • diet
  • genetic studies
• diagnosis
  
  • biomarkers
  • imaging
• classification and prognosis
  
  • clinical staging
  • phenotype symptoms
• clinical trials, treatment and outcomes
  
  • multi-centre RCTs
  • defined outcome measures
  • pelvic pain
  • novel medical treatments
• pathophysiology
  
  • immunomodulators
  • inflammatory mediators
  • macrophage
  • oxidative stress
  • pain
  • angiogenesis
  • lymphangiogenesis
  • stem cells
  • apoptosis
  • miRNA
  • animal and in vitro models
  • transgenic models
  • progestins and SPRMs
  • ovary
  • microbiome
• research policy
  
  • data regestries and Biobanks
  • centres of expertise
  • multidisciplinary approaches
  • lobbying
  • national endometriosis organisations
  • WES and WERF

Question 26

What is their research into genetics and endometriosis?

Answer 26

• large genome-wide association studies (GWAS) have been conducted by various international groups including collaborators at the queensland institute of medical research
  
  • uno et al
  • painter et al
  • nyholt et al
• GWAS is a very powerful approach to discover genes influencing risk for endometriosis
• the studies have identified several association loci (i.e. loci linked with endometriosis risk) and potential candidate endometriosis genes
• next step: how do we use results from the GWAS studies to identify disease mechanisms and drugable targets?

Question 27

What is their research into nerve fibres and pain in endometriosis?

Answer 27

• there is relatively little fundamental or applied research aimed at understanding endometriosis associated pain
• aims:
  
  • to determine whether aberrant innervation is present in the uteri of women with endometriosis, or more broadly in women with pelvic pain
    
    • nerve fibre distribution, density and phenotype in women with different pathologies and pain symptoms
  • to investigate how endometriotic lesions alter the interaction of neurons with the central nervous system
    
    • mechanistic studies investigating how endometriotic lesions affect the cell bodies in the dorsal root ganglia

Question 28

What are the key points?

Answer 28

• HMB occurs in 10-30% of women
  
  • multiple causes
  • mechanisms responsible for HMB are not understood
• uterine fibroids are common benign tumours of the uterine muscle wall
  
  • heterogeneous tumours - size, shape, location, molecular and histological characteristics
  • aetiology unknown
• endometriosis is a common gynacological disorder causing pain and fertility problems
  
  • presence of endometrial tissue outside of the endometrium
  • delay until definitive diagnosis, which requires laparoscopy
  • variable treatments, but disease commonly recurs